title: Next-generation sequence analysis of genes associated with obesity and nonalcoholic fatty liver disease-related cirrhosis in extreme obesity.
abstract: OBJECTIVE
  Genome-wide association studies (GWAS) have led to the identification of single nucleotide polymorphisms in or near several loci that are associated with the risk of obesity and nonalcoholic fatty liver disease (NAFLD). We hypothesized that missense variants in GWAS and related candidate genes may underlie cases of extreme obesity and NAFLD-related cirrhosis, an extreme manifestation of NAFLD.
  
  
  METHODS
  We performed whole-exome sequencing on 6 Caucasian patients with extreme obesity [mean body mass index (BMI) 84.4] and 4 obese Caucasian patients (mean BMI 57.0) with NAFLD-related cirrhosis.
  
  
  RESULTS
  Sequence analysis was performed on 24 replicated GWAS and selected candidate obesity genes and 5 loci associated with NAFLD. No missense variants were identified in 19 of the 29 genes analyzed, although all patients carried at least 2 missense variants in the remaining genes without excess homozygosity. One patient with extreme obesity carried 2 novel damaging mutations in BBS1 and was homozygous for benign and damaging MC3R variants. In addition, 1 patient with NAFLD-related cirrhosis was compound heterozygous for rare damaging mutations in PNPLA3.
  
  
  CONCLUSIONS
  These results indicate that analyzing candidate loci previously identified by GWAS analyses using whole-exome sequencing is an effective strategy to identify potentially causative missense variants underlying extreme obesity and NAFLD-related cirrhosis.
authors.affiliation: Geisinger Obesity Research Institute, Geisinger Clinic, Danville, Pa., USA.
authors.forename: Glenn S
authors.initials: GS
authors.lastname: Gerhard
authors.forename: Xin
authors.initials: X
authors.lastname: Chu
authors.forename: G Craig
authors.initials: GC
authors.lastname: Wood
authors.forename: Genevieve M
authors.initials: GM
authors.lastname: Gerhard
authors.forename: Peter
authors.initials: P
authors.lastname: Benotti
authors.forename: Anthony T
authors.initials: AT
authors.lastname: Petrick
authors.forename: Jon
authors.initials: J
authors.lastname: Gabrielsen
authors.forename: William E
authors.initials: WE
authors.lastname: Strodel
authors.forename: Christopher D
authors.initials: CD
authors.lastname: Still
authors.forename: George
authors.initials: G
authors.lastname: Argyropoulos
mesh_terms: D000328:Adult; D019943:Amino Acid Substitution / Q000235:genetics; D059472:Exome / Q000235:genetics; D005234:Fatty Liver / Q000150:complications / Q000235:genetics*; D005260:Female; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006801:Humans; D008103:Liver Cirrhosis / Q000150:complications / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D065626:Non-alcoholic Fatty Liver Disease; D009767:Obesity, Morbid / Q000150:complications* / Q000235:genetics*; D017422:Sequence Analysis, DNA / Q000379:methods*